Felodipine nanosuspension: a faster in vitro dissolution rate and higher oral absorption efficiency

In the present work, nanocrystals were prepared to improve oral bioavailability of felodipine. Several important formulation factors and process parameters were explored, optimized and analyzed systematically. The prepared nanocrystals were characterized for morphology, particle size, zeta potential, possible crystallization changes, release behavior and oral absorption. The morphology of the obtained nanocrystals was found to be rod shape. The particle size and zeta potential were 140 ± 10 nm and -29.11 mV, respectively. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis indicated that felodipine had undergone crystal form transition. The dissolution rate of felodipine was significantly increased and the AUC_0 -t value of felodipine colloidal dispersion in beagle dogs was approximately 1.6-fold greater than that of the commercial tablets. Nanocrystals impose a faster dissolution rate and higher oral absorption efficiency than raw crystals, and show great potential as an effective strategy for improving oral bioavailability of poorly soluble drugs.     

Formulation of nimodipine nanocrystals for oral administration

The aim of this paper is to optimize nimodipine (NMD) nanocrystals (NCs) for oral administration. The effects of independent process variables (microprecipitation temperature, shearing speed, shearing time, homogenization pressure and number of cycles) on the particle size have been studied. Experiments were conducted to optimize the formulation composition. A single factor exploration was used to screen the primary stabilizers. Then, the selected polymers/surfactants were further optimized using an L9 (3⁴) orthogonal design. The optimal formulation was composed of NMD (0.7 %, w/v), F127 (0.4 %, w/v), HPMC-E5 (0.1 %, w/v), and sodium deoxycholate (0.05 %, w/v) and was rod-shaped as shown by SEM observations, and it had a particle size of 833.3 ± 20.6 nm, determined by laser diffraction. These aqueous NCs were physically stable for 15 days. To further improve the stability, the NCs were freeze-dried. The powder obtained exhibited acceptable flowability and was physically stable for at least 24 months. Additionally, the NMD NCs displayed much higher dissolution profiles than the bulk drug. The pharmacokinetic results showed that the relative bioavailability was 397 % in comparison with Nimotop^®, suggesting that NCs are an efficient strategy for improving the oral bioavailability of poorly water-soluble drugs.     

Bicalutamide nanocrystals with improved oral bioavailability: in vitro and in vivo evaluation

Context: Bicalutamide (BCT) is an antiandrogenic compound belonging to Biopharmaceutics Classification System (BCS) class II drug. Thus it has limited aqueous solubility and hence limited oral bioavailability.

Objective: The purpose of the present investigation was to obtain stable nanocrystals of BCT with improved kinetic solubility, dissolution and pharmacokinetic profiling.

Materials and methods: BCT nanocrystals were prepared by antisolvent precipitation method using Soluplus, a novel amphiphilic polymer. Nanocrystals were characterized for particle size, powder X-ray diffraction analysis (PXRD), in vitro dissolution, in vivo pharmacokinetic profile and stability.

Results and discussion: The obtained nanocrystals had particle size of 168 nm and were spherical in shape. The nanocrystals exhibited fivefold increase in kinetic solubility as compared to pure drug and 85% dissolution in 60 min. PXRD studies established the retention of crystalline polymorphic form II. The in vivo pharmacokinetic study demonstrated that the C_max and AUC of nanosized BCT were about 3.5 times higher as compared to pure drug.

Conclusion: Nanosizing of BCT significantly improved the pharmacokinetic profile of the drug administered to rats. Prepared nanocrystals were found to be stable over the entire stability period. Thus the use of amphiphilic polymer like Soluplus singularly helped in efficient size reduction and stabilization of the drug.     

Kinetic solubility and dissolution velocity of rutin nanocrystals

Lyophilized rutin nanocrystals were intensively evaluated regarding their physicochemical properties with respect to particle size analyses, crystallinity, kinetic solubility and dissolution behavior. The particle size was determined by photon correlation spectroscopy (PCS) and laser diffraction (LD). DSC and X-ray diffraction were used to study the crystalline state of rutin nanocrystals. In a period of 1 week, the kinetic solubility was determined using a shaker at 25 °C. DSC and X-ray diffraction analyses showed that lyophilized rutin nanocrystals prepared by high pressure homogenization remained in crystalline state. Lyophilized rutin nanocrystals could be re-dispersed completely in water and the kinetic solubility in water increased to 133 μg/ml.. Lyophilized rutin nanocrystals were almost completely dissolved within 15 min in water, buffer of pH 1.2 and buffer of pH 6.8. In contrast, only 70% of rutin raw material (rutin microcrystals) was dissolved within 15 min. The superior physicochemical properties of rutin nanocrystals should overcome the absorption problem in the gastrointestinal tract and increase the bioavailability.     

Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs

Danazol is a poorly water soluble compound (10 μg/ml) that demonstrates poor bioavailability. The impact on bioavailability of increasing the area for dissolution by decreasing drug crystal particle size to less than 200 nm and stabilizing the particles to prevent agglomeration in the GI tract has been evaluated. A randomized three-way crossover study was conducted in fasted male beagle dogs to compare absolute oral bioavailability of danazol from three formulations. The three formulations examined were: A, an aqueous dispersion of nanoparticulate danazol (mean particle size 169 nm); B, danazol-hydroxypropyl-β-cyclodextrin (HPB) complex; C, an aqueous suspension of conventional danazol particles (mean particle size 10 μm). The three formulations were administered (200 mg) at 1 week intervals, and a fourth leg was conducted using intravenous danazol-HPB at a dose of 3 mg/kg. Plasma samples were obtained over the course of 24 h and analyzed by SPE-HPLC. Absolute oral bioavailability of each formulation was determined by comparison of oral AUC values to intravenous AUC values in the same dog, normalized to a 20 mg/kg dose. Absolute bioavailabilities of the three formulations were: nanoparticulate danazol, 82.3 ± 10.1%; cyclodextrin complex, 106.7 ± 12.3%; conventional danazol suspension, 5.1 ± 1.9%. The bioavailabilities of nanoparticle dispersion and cyclodextrin complex are not significantly different (P = 0.05) suggesting that the nanoparticle dispersion had overcome the dissolution rate limited bioavailabilty observed with conventional suspensions of danazol. This approach should have general applicability to many poorly soluble drugs with dissolution rate-limited absorption.     

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, C_max, and lower T_max than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.     

Enhanced solubility and bioavailability of flurbiprofen by cycloamylose

The effect of cycloamylose on the aqueous solubility of flurbiprofen was investigated. To improve the solubility and bioavailability of flurbiprofen (poor water solubility), a solid dispersion was spray dried with a solution of flurbiprofen and cycloamylose at a weight ratio of 1:1. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with a commercial product. Cycloamylose increased solubility of flurbiprofen approximately 12-fold and dissolution of it by 2-fold. Flurbiprofen was present in an unchanged crystalline state, and cycloamylose was a solubilizing agent for flurbiprofen in this solid dispersion. Furthermore, the dispersion gave higher AUC and C_max values compared with the commercial product, indicating that it improved the oral bioavailability of flurbiprofen in rats. Thus, the solid dispersion may be useful to deliver flurbiprofen with enhanced bioavailability without changes in crystalline structure.     

柚皮素纳米晶体的制备及体外性质研究

目的:制备一种新型的柚皮素纳米晶体并对其进行表征和体外评价。方法:通过高压均质法制备柚皮素纳米结晶;对制备得到的柚皮素纳米晶体进行粒径测定、DSC分析、X-射线衍射分析和傅里叶红外图谱分析,并测定柚皮素纳米晶体的溶解度和体外溶出度。结果:柚皮素纳米晶体的平均粒径为(467±12) nm,DSC、X-射线衍射及傅里叶红外图谱结果表明将柚皮素制备成柚皮素纳米结晶并未改变药物的晶型和化学结构,溶解度和体外溶出度实验结果表明,与柚皮素原料药相比,柚皮素纳米晶体的溶解度和溶出度均有显著地提高。结论:本文通过制备柚皮素纳米晶体,显著地提高了柚皮素的溶解度和体外溶出度,为柚皮素的临床应用提供了新选择。     

Pharmaceutical particle technologies: An approach to improve drug solubility,dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.     

介孔复合硅微球的制备及载药性质

目的制备介孔复合硅(CaO-SiO2-P2O5)微球,考察其作为水难溶性药物载体提高水难溶性药物的分散性及溶出度的优势。方法采用sol-gel方法制备介孔CaO-SiO2-P2O5微球,以扫描电镜及氮气吸附-脱附等方法分析表征载体的外观形貌、比表面积及孔径分布;选取尼莫地平为模型药物,以溶剂浸渍挥干法载药制得药物固体分散体;采用热分析、氮气吸附-脱附曲线分析以及溶出度实验研究药物固体分散体的基本性质。结果制得的复合硅载体的形貌近球状,粒径大小主要分布在3～6μm,载体的比表面积为637.34 m2.g-1,孔容为1.371 8 cm3.g-1,孔径分布主要集中在10～12 nm。当药物和载体的质量比为1:4时,药物能够被包埋分散于载体内部,且以无定型的形式存在,45 min尼莫地平累计溶出达80%。结论介孔CaO-SiO2-P2O5微球有望成为水难溶性药物的优良载体。     

High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers

A nebulized dispersion of amorphous, high surface area, nanostructured aggregates of itraconazole (ITZ):mannitol:lecithin (1:0.5:0.2, w/w) yielded improved bioavailability in mice. The ultra-rapid freezing (URF) technique used to produce the nanoparticles was found to molecularly disperse the ITZ with the excipients as a solid solution. Upon addition to water, ITZ formed a colloidal dispersion suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic levels when dosed to mice. The ITZ nanoparticles produced supersaturation levels 27 times the crystalline solubility upon dissolution in simulated lung fluid. A dissolution/permeation model indicated that the absorption of 3mum ITZ particles is limited by the dissolution rate (BCS Class II behavior), while absorption is permeation-limited for more rapidly dissolving 230nm particles. The predicted absorption half-life for 230nm amorphous ITZ particles was only 15min, as a result of the small particle size and high supersaturation, in general agreement with the in vivo results. Thus, bioavailability may be enhanced, by decreasing the particle size to accelerate dissolution and increasing permeation with (1) an amorphous morphology to raise the drug solubility, and (2) permeability enhancers.     

A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs

ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ～11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200?nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.     

Development of novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability

To develop a novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability, various itraconazole-loaded solid dispersions were prepared with water, polyvinylpyrroline, poloxamer and citric acid. The effect of carriers on aqueous solubility of itraconazole was investigated. Their physicochemical properties were investigated using SEM, DSC, and powder X-ray diffraction. The dissolution, bioavailability in rats and stability of solid dispersions were evaluated. Unlike conventional solid dispersion system, the itraconazole-loaded solid dispersion with relatively rough surface did not change crystalline form of drug. Our DSC and powder X-ray diffraction results suggested that this solid dispersion was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in conversion of the hydrophobic drug to hydrophilic form. The itraconazole-loaded solid dispersion at the weight ratio of itraconazole/polyvinylpyrroline/poloxamer of 10/2/0.5 gave maximum drug solubility of about 20 μg/mL. It did not change the crystalline form of drug for at least 6 months, indicating that it was physically stable. It gave higher AUC, C_max and T_max compared to itraconazole powder and similar values to the commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, it would be useful to deliver a poorly water-soluble itraconazole without crystalline change with improved bioavailability.     

尼莫地平固体分散物制备及物相鉴别

目的：制备尼莫地平固体分散物,增加其溶解度和溶出速度。方法：以混合辅料Ｎ为载体采用溶剂分散法制备固体分散物,差热分析,Ｘ－射线粉末衍射,扫描电镜和红外线光谱鉴别药物在载体中的状态,并进行溶出度研究。结果：尼莫地平在载体中以分子或无定型状态存在,载体比例越大,药物溶出越快。结论：尼莫地平－辅料Ｎ固体分散体增溶作用显著。     

交联聚维酮粒度对尼莫地平片溶出度的影响

目的探讨不同粒度交联聚维酮(Polyplasdone)对尼莫地平片溶出度的影响。方法采用不同粒度的交联聚维酮制备尼莫地平片,用紫外分光光度法测定溶出度。结果采用不同粒径的交联聚维酮制备尼莫地平片其溶出度相差甚远,其中粒径在125~74μm范围内的交联聚维酮生产出的尼莫地平片溶出效果最好,30min溶出度为95.74%。结论粒度在125~74μm范围内的交联聚维酮生产出的尼莫地平片体外溶出度最高。     

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.     

Preparation of uniform prednisolone microcrystals by a controlled microprecipitation method

Prednisolone (PDL) microcrystals were successfully prepared by a controlled microprecipitation method. The characterization of PDL microcrystals by SEM and PSD indicated that the hexagonal and tetragonal PDL microcrystals with an average particle size of 1.60 and 1.46 microm could be prepared under a stirring speed of 10,000 rpm at 14 and 4 degrees C, respectively. The morphology and the particle size of PDL could be well controlled, from 1.60 to 6.12 microm for hexagonal microcrystals and 1.46 to 3.90 microm for tetragonal ones, by altering the operating parameters such as temperature, stirring speed and stabilizers. The XRD, TGA-DSC, FT-IR and physical stability studies demonstrated that the as-prepared hexagonal and tetragonal PDL microcrystals with the same pseudopolymorphic form were much more stable in water than the commercial micronized PDL with another crystal form. The dissolution tests showed that the hexagonal and tetragonal PDL microcrystals exhibited significantly enhanced dissolution property when compared to commercial micronized PDL.     

Physical–chemical properties of furosemide nanocrystals developed using rotation revolution mixer

Recently, several approaches have been reported to improve the dissolution rate and bioavailability of furosemide, a class IV drug. However, to the best of our knowledge, none of them proposed nanocrystals. In the last decade, nanocrystals successfully addressed solubility issues by increasing surface area and saturation solubility, both leading to an increase in the dissolution rate of poor water soluble drugs. The preparation of furosemide nanocrystals was by a rotation revolution mixer method. Size distribution and morphology were performed using laser diffraction and scanning electron microscopy, respectively. In addition, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction (XRD) and low frequency shift-Raman spectroscopy allowed investigating the thermal properties and crystalline state. Solubility saturation and intrinsic dissolution rate (IDR) studies were conducted. The thermal analysis revealed lower melting range for the nanocrystals comparing to furosemide. Moreover, a slight crystalline structure change to the amorphous state was observed by XRD and confirmed by low frequency shift Raman. The particle size was reduced to 231?nm with a polydispersity index of 0.232, a 30-fold reduction from the original powder. Finally, the saturation solubility and IDR showed a significant increase. Furosemide nanocrystals showed potential for development of innovative formulations as an alternative to the commercial products.     

尼莫地平固体分散体的研究

目的 制备尼莫地平固体分散体,增加其溶出速度.方法 应用聚乙烯吡咯烷酮（PVP）为载体,采用喷雾干燥制备尼莫地平固体分散体,通过差示扫描量热分析（DSC）和X-射线粉末衍射分析鉴别药物在载体中的存在状态,并进行了体外溶出度研究.结果 尼莫地平在载体中以分子状态存在,尼莫地平固体分散体的溶出度与尼莫地平原料药和原料药载体物理混合物相比有显著提高,载体比例越大,药物溶出越快,药物载体比例为1：3时t50仅0.972 6 min,结论聚乙烯吡咯烷酮（PVP）作为尼莫地平固体分散体的载体载药量大;喷雾干燥工艺重现性好,分散体颗粒无需粉碎可满足各类固体制剂的制备要求,是一种较理想的尼莫地平固体分散体的制备方法.     

Development of novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose, it was prepared using spray-drying techniques with cycloamylose at a weight ratio of 1:1. The effect of cycloamylose on aqueous solubility of ibuprofen was investigated. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with ibuprofen powder. This ibuprofen-loaded solid dispersion improved about 14-fold drug solubility. Ibuprofen was present in an unchanged crystalline state, and cycloamylose played the simple role of a solubilizing agent in this solid dispersion. Moreover, the dispersion gave 2-fold higher AUC (area under the drug concentration-time curve) value compared with a ibuprofen powder, indicating that it improved the oral bioavailability of ibuprofen in rats. Thus, the solid dispersion may be useful to deliver ibuprofen with enhanced bioavailability without crystalline change.